Project Summary The use of monoclonal antibodies (mAbs) for cancer therapy has achieved considerable success, leading to breakthroughs in the treatment of many types of cancer. In most cases cancer mAbs act by distinguishing normal and tumor cells by the extent of elevated expression of the target protein on the tumor cell. As there is no structural difference in the binding epitopes seen on normal and tumor cells, mAbs are still able to bind and effect normal cells, even if the target protein is expressed at low levels. As a result existing mAbs on the market can have significant side effects which disallows use for many patients. Development of numerous mAbs against novel tumor targets have incurred insurmountable hurdles due to off-target effects. The goal of this project is develop mAb-based therapeutics that exhibit superior selectivities and efficacies by combined targeting of proteins that are overexpressed by cancer cells and the presence of tumor- associated aberrant glycosylation. To achieve the goal of tumor specific targeting, we are focused on exploiting a specific glycan structure that is found on the cell surface of most solid tumors including those of the breast, lung and colon. This aberrant glycan exposes protein epitopes on cancer cells that are normally shielded on healthy tissues. There are numerous cell surface proteins that have a high potential of displaying these aberrant glycans and are known to be over-expressed on major cancers. For this proposal we are focusing on a target of a current therapeutic on the market that, while very effective, can cause significant side effects in a number of patients. We will generate an antibody-based therapeutic that addresses problematic toxicity associated with the existing therapeutic. We will use a novel immunogen platform and methodology, termed GTI, to generate mAbs with high affinity and specificity for proteins. These mAbs will be developed in such that they only recognize target proteins when modified with the tumor-specific aberrant glycans. Not only will novel and improved therapeutics result from this project, it will serve as proof of a principle that employing tumor-specific aberrant glycosylation in the context of over-expressed tumor-associated proteins is a defining methodology for the generation of truly tumor-specific therapeutic agents.